Chronic but not acute morphine exposure reversibly impairs spike generation and repetitive firing in a functionally distinct subpopulation of orexin neurons

Orexin (hypocretin) neuropeptides regulate numerous essential functions including sleep/wake

state stability and reward processing. Orexin synthesizing neurons respond to drug cues and undergo

structural changes following persistent drug exposure. Post-mortem brains from opioid users, and

opioid-treated rodents have orexin somata that become ~20 % smaller and ~50% more numerous and

are postulated to promote hyper-motivation for drug-seeking though increased orexin release.

Biophysical considerations suggest that decreased soma size should increase cellular excitability,

however the impact of chronic opioids on firing ability, which drives peptide release, has not been

explored. To test this, we assessed the intrinsic electrophysiological properties of orexin neurons by

whole-cell recordings in slices from male orexin-EGFP mice treated by daily morphine or saline injections

for two weeks. Paradoxically, we found that while daily morphine decreased average soma size, it

impaired excitability in a subpopulation of orexin neurons identified by electrophysiological criteria as

“H-type”, while entirely sparing “D-type” neurons. This impairment was manifest by smaller, broader

action potentials, variable firing and a downscaling of firing gain. These adaptations required more than

a single morphine dose and recovered, along with soma size, after four weeks of passive withdrawal.

Taken together, these observations indicate that daily opioid exposure differentially impacts H-type

orexin neurons and predicts that the ability of these neurons to encode synaptic inputs into spike trains

and to release neuropeptides becomes impaired in conjunction with opioid dependence.